American Society of Hematology Guidelines for Management of Cancer-Associated Thrombosis

Introduction

The risk of venous thromboembolism (VTE) is substantially increased in patients with cancer especially those who are hospitalized, in active treatment, and with major medical comorbidities.¹ VTE in patients with cancer is associated with serious adverse consequences, including VTE recurrence, major bleeding and early mortality.² Since its derivation, the Khorana risk score for cancer-associated thrombosis has been validated in multiple prospective and retrospective studies.^3-5 Several randomized controlled trials (RCTs) of primary prevention in the ambulatory cancer setting for those at increased risk for VTE have confirmed that low-molecular-weight heparins (LMWHs) can significantly reduce the risk of VTE with only a modest increase in major bleeding risk.⁶

Recent RCTs and meta-analyses have directly compared direct oral anticoagulants (DOACs) with LMWH for the treatment of established VTE in patients with cancer.^7-9 While the absolute risk differences were small, the RCTs and overview demonstrated that the risk of recurrent VTE was lower while the risk of bleeding greater with DOACs compared with LMWH. Subsequently, the Khorana risk score has been used to select high-risk ambulatory cancer patients for accrual to two thromboprophylaxis trials comparing low-dose DOACs with placebo in patients receiving chemotherapy for cancer at intermediate- or high-risk for VTE (AVERT and CASSINI).^10,11

Pooled results from these DOAC placebo-controlled thromboprophylaxis trials in higher risk ambulatory patients receiving cancer therapy demonstrated a significant reduction in overall VTE incidence in those receiving a DOAC prophylactically.¹² A small, nonsignificant increased risk of major bleeding and clinically relevant non-major bleeding (CRNMB) with DOACs was observed.

 

Clinical Practice Guidelines for the Treatment and Prevention of VTE

Several clinical practice guidelines addressing VTE treatment and prevention in patients with malignant disease have been updated, including that from the American Society of Clinical Oncology (ASCO), which was established nearly 15 years ago.^13,14 The latest of these are new guidelines for the prevention and treatment of VTE in patients with cancer from the American Society of Hematology, which has now issued a total of 10 guidelines on the management of VTE in a range of clinical situations.

ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The GRADE approach was used to assess evidence and make recommendations, which were subject to public comment. These guidelines provide 34 recommendations covering appropriate thromboprophylaxis in hospitalized medical patients with cancer, those undergoing a surgical procedure and in ambulatory patients with cancer receiving systemic therapy.

The recommendations also address the use of anticoagulation for the initial (first week), short- (subsequent 3–6 months) and long-term (>6 months) treatment of VTE in patients with cancer, including those with central venous catheter and patients with recurrent VTE despite anticoagulation treatment. Abbreviated summaries of the final recommendations from the ASH VTE Cancer Guidelines are summarized in Table 1.

 

Table 1. ASH Recommendations for the Prevention and Treatment of Venous Thromboembolism in Patients with Cancer – Data taken from Lyman et al¹⁵

Primary prophylaxis in hospitalized medical patients with cancer without VTE Pharmacological thromboprophylaxis with LMWH over unfractionated heparin (UFH) preferred without addition of mechanical thromboprophylaxis Pharmacological thromboprophylaxis should be discontinued at the time of hospital discharge

Thromboprophylaxis in patients with cancer undergoing surgery Pharmacological prophylaxis with LMWH or fondaparinux rather than mechanical thromboprophylaxis in those at low bleeding risk Mechanical rather than pharmacological thromboprophylaxis in those at high bleeding risk Combination of mechanical and pharmacologic thromboprophylaxis in those with high thrombosis risk Post-operative thromboprophylaxis preferred over pre-operative thromboprophylaxis Continuing pharmacological thromboprophylaxis post discharge rather than discontinuing at the time of hospital discharge

Thromboprophylaxis in ambulatory patients with cancer receiving systemic therapy No thromboprophylaxis in ambulatory patients receiving systemic cancer therapy at low risk of thrombosis No thromboprophylaxis or pharmacologic prophylaxis with apixaban or rivaroxaban in ambulatory patients receiving systemic cancer therapy at intermediate risk of thrombosis Pharmacologic prophylaxis with LMWH, apixaban or rivaroxiban in ambulatory patients receiving systemic cancer therapy at high risk of thrombosis. Pharmacologic prophylaxis with low-dose acetylsalicylic acid, fixed low-dose vitamin K antagonists (VKA) or LMWH in patients with multiple myeloma receiving lenalidomide, thalidomide or pomalidomide-based regimens.

Thromboprophylaxis in patients with cancer with central venous catheter No pharmacologic thromboprophylaxis in patients with cancer and a central venous catheter

Initial treatment (first week) in patients with active cancer and VTE Treatment with LMWH, apixaban or rivaroxaban for initial treatment of VTE in patients with cancer

Short-term treatment (3–6 months) in patients with active cancer Treatment with apixaban, edoxaban or rivaroxaban for short-term treatment of VTE in patients with active cancer Treatment with LMWH for short-term treatment of VTE in patients with active cancer when a DOAC is not available or contraindicated Pharmacologic treatment for short-term treatment of incidental pulmonary embolism (PE) in patients with active cancer Pharmacologic treatment for short-term treatment of sub-segmental PE in patients with active cancer Pharmacologic treatment OR observation for short-term treatment of visceral/splanchnic vein thrombosis in patients with active cancer Retain central venous catheter in patients with cancer and central venous catheter-related VTE receiving anticoagulant treatment. Continue therapeutic LMWH or increase dose to supra-therapeutic dose LMWH in patients with cancer and recurrent VTE despite receiving therapeutic LMWH Do not use inferior vena cava filter in patients with cancer and recurrent VTE despite anticoagulation treatment.

Long-term treatment (>6 months) in patients with active cancer and VTE Secondary thromboprophylaxis for long-term management of VTE in patients with active cancer and VTE. Continue indefinite secondary thromboprophylaxis with either a DOAC or LMWH beyond 6 months in patients with active cancer and VTE.

 

Evidence-based guidelines from ASH and other professional organizations can provide clinicians with a balanced resource for the use of anticoagulants in the specific management of patients with cancer. The high level of concordance in updated recommendations across currently available clinical practice guidelines is reassuring. However, further efforts are needed to improve the dissemination, implementation and utilization of available guidelines in order to bring clinical practice into compliance with current recommendations. While the use of recently validated clinical risk models for VTE among ambulatory cancer patients is promising, new biomarkers for VTE and bleeding complications are needed to further improve selection of high-risk patients for more individualized or personalized prophylactic strategies. It will only be through optimal application of current strategies along with increased investment into basic and translational clinical research that further reductions in the morbidity and mortality associated with thromboembolic complications in patients with cancer can be realized.

 

Conclusion

The recent ASH clinical practice guideline recommendations include the use of thromboprophylaxis with LMWHs in hospitalized patients with cancer. The use of LMWH, apixaban or rivaroxaban is recommended in ambulatory patients receiving systemic cancer therapy at high risk for thrombosis. Either no thromboprophlaxis or prophylaxis with apixaban or rivaroxaban is instead recommended in patients receiving systemic cancer therapy at intermediate risk for thrombosis.

In patients undergoing major cancer surgery, thromboprophylaxis with LMWH or fondaparinux with or without mechanical prophylaxis is recommended in those with low bleeding risk while mechanical prophylaxis alone is encouraged in those with at high bleeding risk. Initial treatment with LMWH, apixaban or rivaroxaban is recommended for the initial (first week) of treatment of thrombosis of patients with active cancer. Short-term treatment (3–6 months) and long-term secondary prophylaxis (>6 months) with LMWH or a DOAC are recommended for patients with active cancer and established VTE. Finally, clinical decision-making related to thromboprophylaxis or treatment of VTE in patients with cancer should be based on an assessment of the individual patient’s risk for both thrombosis and major bleeding following full discussion of the potential benefits and harms.

It is essential to understand that patients may have different values and preferences than those held by their clinician with respect to the goals of anticoagulation and the assessment of risks and benefits, which may change over time and must be continuously reassessed.

 

References

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